Biphenylyl pyrazole compounds

ABSTRACT

Pyrazole compounds of the formula   WHEREIN R1 and R2 are hydrogen, methyl or ethyl, B is   AND X is hydrogen or halogen. These compounds possess analgesic and anti-inflammatory properties.

United States Patent 1 1' Beregi et al.

[ 51 Apr. 3, 1973 [54] BIPHENYLYL PYRAZOLE COMPOUNDS [75] Inventors:Laszlo Beregi, Boulogne S/Seinej Pierre Hugon, Rueil-Malmaison;Jean-Claude Le Douarec, Suresnes, all of France [7-3] Assignee: Societeen Nom' Collecti'f Science Union et Cie, Soeiete Francaise Medicale,Suresnes, France 22 Filed: June 28,1971 Y [21] A'ppl. No.: 157,727

[30] Foreign Application Priority Data July 13,1970 Great Britain..33,824 /70 [52] US. Cl. ..260/3l0 It, 266/544 M, 424/273 [51] Int. Cl...C07d 49/18 [58] Field of Search ..260/3 10 R [5 6] References CitedOTHER PUBLICATIONS Matsoyan et al. Chem. Abst. Vol.72, No. 90362h(1970). QDLASI Reid et al. Chem. Abst, Vol. 53, column 1314 (I959)QDl.A5l

Primary Examiner-Natalie Trousof Attorney-Go rdon W. Hueschen et al.

57 I ABSTRACT I (rm cm (31H: -13, CH7-, CH-, or CH- and X is hydrogen orhalogen.

These compounds possess analgesic and anti-inflammatory properties.

4 Claims, No Drayvings BIPHENYLYL PYRAZOLE COMPOUNDS The presentinvention provides pyrazole compounds of the general formula I:

A: X I

wherein:

R and R,, which are the same or different are selected from the groupconsisting of a hydrogen atom,'a methyl radical and an ethyl radical;

B is selected from the group'consisting of a radical, a CH radical, a

radical, and a X II I wherein B and X have the meanings given, above,

with a pyrazole of the general formula III:

Rz III wherein R, and R have the meanings given above.

The following examples illustrate the invention. All parts were given byweight and the melting points were determined by the Kofler method.

EXAMPLE 1 1 -(biphenyl-4-yl-acetyl)-3,S-dimethyl-pyrazole -CHs To asolution of 23.9 parts of 3,5-dimethyl-pyrazole in 500 parts ofanhydrous ether there were added, in the course of 30 minutes withstirring, 28.7 parts of biphenyl-4-yl-acetyl chloride in 500 parts ofanhydrous ether.

The reaction mixture was refluxed for 1 hour, then cooled and theprecipitated 3,5-dimethylpyrazole hydrochloride was filtered off. Thefiltrate was evaporated in vacuo and the residue was crystallized fromparts of anhydrous ethanol.

There were obtained 27.5 parts ofl-(biphenyl-4-ylacetyl)-3,5-dimethylpyrazole, melting at 64-66 C.

EXAMPLES 2 9 The following compounds were prepared by the method ofExample 1.

2. l [a-(biphenyl-4-y l )-propionyl 3 ,5 -dimethylpyrazole, M.P. 73 C(petroleum-ether), starting from biphenyl-4-yl-propionyl chloride and3,5- dimethyl-pyrazole.

3. 1-[a-(biphenyl-4-yl)-butyryl]-3 ,S-dimethylpyrazole, M.P. 77 C(isopropanol), starting from a (biphenyl-4-yl)-butyryl chloride and 3,5-dimethyl-pyrazole.

4. l-[(4'-fluorobiphenyl-4-yl)-acetyl]-3,5-dimethylpyrazole, M.P. 7374 C(isopropanol), starting from (4-fluorobiphenyl-4-acetyl chloride and3,5- dimethyl-pyrazole.

5. l-[a-(4'-fluorobiphenyl-4-yl)-propionyl]-3,5-

dimethyl-pyrazole, M.P. 596l C (isopropanol), starting froma-(4-fluorobiphenyl-4yl)-propionyl chloride and 3,5-dimethyl-pyrazole.

. l-[a-(biphenyl-4-yl)-butyryl]-pyrazole, MP. 117 C (isopropanol),starting from a-(biphenyl-4-yl)- butyryl chloride and pyrazole.

7. l-(biphenyl-4-yl-acetyl)-3,5 diethyl-pyrazole, starting frombiphenyl-4-yl-acetyl chloride and 3,5-diethyl-pyrazole.

8. l-[ 2 '-chlorobiphenyl-4-yl) acetyl1-3-ethylpyrazole, starting from(2'-chlorobiphenyl-4-yl) acetyl chloride and 3-ethyl-pyrazole.

9. l-[a-(biphenyl-4-yl)-acryloyl]-pyrazole, starting froma-(biphenyl-4-yl)-acryloyl chloride and pyrazole.

The compounds of the present invention possess valuable pharmacologicaland therapeutic properties, especially analgesic and anti-inflammatoryproperties in general and topical use.

Their toxicity was studied in mice by oral route and the LD was foundbeing in all cases superior to 2,000 mg/Kg.

The anti-inflammatory activity of the new compounds was evidenced byseveral methods, such as described by C.A. Winter et al. (Proc. Soc.Exp. Biol. Med. 3, 544,- 1962) or J. Hillebrecht (Arz. Fschg. 4, 607,1954) on the plantar oedema of the rats paw induced by carrageenin or byKaolin, further by the cot ton pellet test of R. Meier et al.(Experientia, 6, 4 69, 1950) and by the erythema induced by ultravioletrays. In the carrageenin test the oedema was decreased from 24 to 82percent by doses of 5 to 20 mg/Kg P.O. of the new compounds. TheKaolin-oedema was inhibited up to 62 percent with a treatment of 40 to70 mg/Kg P.O.

during three days. These results show the superiority of the newcompounds in comparison with the wellknown anti-inflammatory agents suchas, phenylbutazone, niflumic and mefenamic acid.

Analgesic properties of the new compounds were observed by the hot platemethod of Woolf G. and Mac- Donald A.D. modified by E. Adami et E.Marazzi tablets, capsules, suppositories, ointments or solutionsfororal, rectal, topical or parenteral administration at doses of 50 to 500mg, preferably 200-300 mg, one to five times a day.

What we claim is l. A pyrazole compound of the formula wherein R and R,,which are the same or different, are selected from the group consistingof hydrogen, methyl and ethyl;

5 B is selected from the group consisting of:

(EH1 (IJHJ (3111.5 CII2. CII. and CII-- 0 and X is selected from thegroup consisting of hydrogen and halogen.v

2. A compound of claim 1 which is l-(biphenyl-4-ylacetyl)-3,5-dimethylpyrazole.

3. A compound of claim 1 which is l-[a-(4'-fluorobiphenyl-4-yl)-propionyl]-3,5 dimethyl-pyrazole.

4. A compound of claim 1 which is l-[a-(biphenyl-4-yl)-butyryl]-pyrazole.

2. A compound of claim 1 which is 1-(biphenyl-4-yl-acetyl)-3, 5-dimethylpyrazole.
 3. A compound of claim 1 which is 1-( Alpha-(4''-fluorobiphenyl-4-yl)-propionyl)-3,5 dimethyl-pyrazole.
 4. Acompound of claim 1 which is 1-( Alpha-(biphenyl-4-yl)-butyryl)-pyrazole.